Platelets are anucleated blood cells derived from megakaryocytes that are essential for proper hemostasis and thrombosis. Apoptosis-like processes have also been linked to platelet biogenesis (i.e. thrombopoiesis) and aging (i.e. senescence). The processes of apoptosis have been extensively studied in nucleated cells; however, its role in anucleated cells is less defined. Cytochrome c, caspase-9, caspase-3, and APAF-1 have been reported to be expressed in platelets indicating that platelets contain the necessary apoptotic machinery to execute programmed cell death. Several studies have demonstrated that the Bcl-2 family proteins (i.e. Bax, Bak, Bcl-XL, and Bcl-2) are also expressed in platelets. The Bcl-2 family of proteins are the key regulators of mitochondria-dependent apoptosis in nucleated cells and consists of both anti-apoptotic (Bcl-XL, Bcl-2, Bcl-w, Al, Mcl-1) and pro-apoptotic (Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, Puma) members. The decision for a cell to progress through the apoptotic pathway is dependent on the interplay between these pro-survival and pro-death proteins. The pro-apoptotic proteins propagate the death signal by ultimately inducing permeabilization of the mitochondrial membrane, release of cytochrome c and caspase activation. The anti-apoptotic family members exert their protective effects by directly binding to and sequestering their pro-apoptotic counterparts. Inhibition of anti-apoptotic Bcl-2 protein family members is known to induce apoptosis in cells that are dependent on these proteins for survival.
Although circulating platelet production is a normal physiological process, a number of diseases are caused or exacerbated by excess of, or undesired activation of, platelets. There is therefore an existing need in the therapeutic arts for methods of reducing the number of platelets in mammals and preventing or treating pro-thrombotic conditions and diseases that are characterized by an excess of, or undesired activation of, platelets.